LifeTime COVID-19 Interviews

"Nevertheless, many continued hoping that the epidemic would soon die out and they and their families be spared. Thus they felt under no obligation to make any change in their habits as yet."

Albert Camus

The Plague, translated from the French by Stuart Gilbert

The current coronavirus pandemic demonstrates in an alarming way how important it is to understand and prepare for the fight against infectious diseases. As this is an integral part of the LifeTime roadmap, the initiative counts among its members actors at the forefront in the research on COVID-19. In a series of interviews, which will be regularly published here, we want to share with you the thoughts and recommendations of leading experts from LifeTime.

We learn from today so we can be prepared for tomorrow!

"It is important to invest in medicine and science"

Interview with Dr. Luis Serrano,
Director of Centre for Genomic Regulation (CRG), Barcelona. CRG is a biomedical research institute with programmes on Bioinformatics and Genomics, Cell and Developmental Biology, Gene Regulation, Stem Cells, and Cancer and Systems Biology.

Setting up a pipeline that involves reprogramming the robots we have, establishing the safety procedures for the personnel involved, coordinating with the health authorities and agree on how to collect the samples and how to send back the results. Essentially establishing a safe, and reliable pipeline.

We did not change the nature of the institute, we transformed an S2 room into a place for RNA extraction and a big seminar room adjacent to it as a storage place for reagents, printing the barcodes, reading the barcodes, etc. We have decreased by 50% the capacity of the genomics facility in order to use the personnel and robots for preparing the PCR plates and doing the RT-PCR. The rest of the institute can continue doing business as usual within the current government restrictions.

For RNA extraction, we have two robots, one using columns and the other magnetic beads. We have a robot for dispensing lysis buffer in tubes that are sent to the hospitals and another to convert the 96 well plates into 384plates. Finally, we have six quantitative PCR machines and a printer that can print several thousand labels with barcodes per day.

It is quite exciting and rewarding. Firstly and more importantly, we hope to contribute to stopping the spread of the virus by doing massive tests on the population. Secondly, we are showing the public the importance of having research institutes and trained personal.

We have several ongoing or planned projects on the coronavirus. We will keep all patient samples frozen to sequence the virus and thanks to the barcoding we could access to blood samples of the patients and do sequencing so we will be able to see if there are special virulent versions of the virus, as well as the importance of human variability in virus susceptibility. We are also expressing viral proteins in human cells properly glycosylated to be used for screening people that have passed the disease. Moreover, we look forward to harnessing the expertise of our researchers in single-cell analyses (e.g. Holger Heyn) and bioinformatics (eg. Marc A. Marti Renom) to implement the LifeTime approach with our European partners.

Everyone claims that this pandemic will change our world and I imagine it could have an impact on science. At least, in my case, I see that we could live with much less traveling and more conferences. I hope that the European politicians will realize how important it is to invest in medicine and science, not only for finding new therapies but to be ready with equipment, resources, and trained personnel to fight future new viral or bacterial outbreaks.

"COVID-19 is emerging as having clear sex and gender dimension"

Interview with Dr. Susanna Chiocca,
Director of Viral control of cellular pathways and biology of tumorigenesis Unit, European Institute of Oncology, Milan

While preliminary sex-disaggregated data show that the proportion of COVID-19 cases in males and females is approximately equal, there is already a clear sex difference in mortality and disease aggressiveness (REF). Indeed, more men are dying perhaps because of sex-related immunological or hormonal differences, and/or gendered differences, such as higher smoking rate in men than in women in China.

However, data on smoking and prevalence or severity of the disease are still fragmented (REF). In support of a possible hormonal difference, sex-based differences were found in a murine model of SARS-CoV infection, the virus responsible for the 2002-2003 SARS epidemic. Male mice were more susceptible to SARS-CoV infection compared to age-matched females, most likely due to estrogen signaling protection of lethal viral infection on female mice (REF: doi:10.4049/jimmunol.1601896).

Other aspects to consider are the risk of exposure of the different genders because of cultural and biological differences and social behaviors (handwashing, face-eye and other exposed body parts touching, general awareness of proper measures to take for protection, etc). The percentage of people tested and the way the testing for viral presence is carried out may also differ among the genders.

Not only in my group but in the whole department and hospital we are thinking of how to exploit our know-how for better viral testing, as well as towards the understanding of the pathogenesis of SARS-CoV2. We are currently working on various applications addressing many aspects involved in this disease. We are a cancer institute so, of course, since COVID-19 cancer patients are most likely at higher risk of incurring in more severe events, compared with patients without cancer, our hospital has devised ways to protect them and of course to isolate them from other patients.

COVID-19 is emerging as having clear sex and gender dimension. As in all disease outbreaks, it is of utmost importance to recognize the impact of the epidemics/ pandemics with also a sex and gender lens. For example, for the development of proper therapeutics, the sex and gender dimension must be taken into account, since the outcome of SARS-CoV2 infection may differ in the two sexes, as well as the sex differences associated with pharmacodynamic effects of possible drugs on the body and with pharmacokinetics (drug absorption, distribution, metabolism, and elimination). Importantly, any defined clinical trial should be designed to be absolutely equitable including both women and men, tracking as much as possible all those behaviours that might be gender-related (smoking and/ or the life-style habits).

"The approaches initiated during an outbreak of a new virus should be pursued even if the epidemic goes away"

Interview with Félix A. Rey, head of Department of Virology,
Institut Pasteur and director of research at French National Centre for Scientific Research (CNRS)

My research aims at understanding in detail the epitopes that are targeted by the human antibodies elicited by the infection. In collaboration with colleagues from the immunology Department at the Institut Pasteur, we are trying to identify the antibodies that have the broadest possible cross-reactivity against betacoronaviruses, and yet retain their neutralization capacity. This information will allow us to carry out an epitope-focused vaccine approach aimed at generating immunogens that elicit preferentially this type of antibodies. We do not know if a vaccine will be available before the end of this pandemic, but the pandemic potential of betacoronaviruses has been amply demonstrated. A different member of this genus could in the future emerge, and the best protection would be a vaccine eliciting a broad immunity against these viruses.

One of the lessons is that the approaches initiated during an outbreak of a new virus should be pursued even if the epidemic goes away quickly, as was the case in 2003 with SARS-CoV-1. If all the research activity initiated at that time had not been discontinued once the virus disappeared, we would have been far better equipped to contain the SARS-CoV-2 outbreak.

Beyond vaccine design, the structural data can provide a very useful guide to a rational approach to identify small molecules with therapeutic potential. For instance, we are doing a high-throughput screen of compounds with the ability to interfere with the interaction between the SARS-CoV-2 spike protein and the ACE2 receptor. The compounds are derived from a library designed by chemoinformatics combined to a machine learning approach, which uses a model learned by the examination of all structures of protein/protein complexes available in the Protein Data Bank. All hits will be studied by X-ray crystallography or cryo-electron microscopy to understand in detail the mode of interaction of the compound either with the spike protein or with the ACE2 receptor and identify potential modifications by medicinal chemistry to improve the compound’s potency. Similar approaches are being followed by my colleagues at the institute targeting the coronavirus RNA polymerase, as well as the several viral encoded proteases. As an RNA virus, coronaviruses have a tendency to mutate and develop quick resistance to a single treatment. Targeting several steps of the viral cycle is therefore crucial. An example is that of the hepatitis C virus, also an RNA virus, which can now be cured by a cocktail of molecules designed to target the viral protease, the polymerase, and the viral protein that blocks the innate antiviral reaction of the cell. We anticipate that a similar approach could work for coronaviruses as well.

It is not possible to predict which virus will cause the next pandemic, although some viruses are more likely than others. The European Commission could fund basic research aimed at unifying our knowledge on the different families of RNA viruses, as any of them could be at the source of new emerging human pathogenic viruses. In particular, zoonotic viruses that can spill over into the human population. For some of these families, extremely little scientific information is available today. It would be important to identify the epitopes of the neutralizing antibodies for at least one member of each family. Even if different viruses in a given family cannot be neutralized by the same antibodies, the understanding from other members of the epitopes that need to be targeted would be extremely useful in case of an emergence. Also, knowing the cell surface receptor that at least some viruses in each family use for entry could be extremely useful. In other words, it would be important to set up a list of the minimal information required in case a virus from any of the identified families were to emerge, to be able to act quickly. The European Commission could be extremely helpful in setting up such a program.

I think the task force could be highly instrumental in advising the European Commission of the type of programs that should be run for better preparedness in case of other pandemics or even more focused viral outbreaks, like the Ebola outbreak of 2014 in West Africa.

"Collaboration between countries and leading research institutes in Europe is the key"

In Leuven, Belgium we have set up a study called COntAGIouS, in which we are studying host-immune response to the SARS-CoV-2. Deep-immune profiling will be performed using scRNA-seq approaches, CyTOF, and FACS. We are collecting peripheral blood, but also bronchial alveolar lavage (BAL) samples and lung tissue (warm autopsy from deceased patients). Once all data will be collected, machine learning approaches to integrate the data will be used. The project is a unique collaborative effort set up by pneumologists, intensive care unit specialists and more basic researchers, including myself (at VIB). In one week’s time, we were able to already collect these data from 15 COVID-19 patients and our recruitment rate is only increasing. We are lucky to have an L3 unit in our university and we have transferred our whole single-cell setup into this facility so we can process a large number of samples from COVID19 patients. In parallel, we collect the same material from patients with other lung infections (e.g., influenza) so we can compare what makes SARS-CoV-2 different from other infections. We also collect DNA from all patients, to better understand the genetic susceptibility to SARS-CoV-2 in the population.

COVID-19 samples are collected in the intensive care unit (severe COVID-19) but also in the regular wards (non-severe COVID-19). By collecting samples at serial timepoints, we hope to learn which molecular pathways and genes prevent non-severe patients from developing severe disease. We also hope to understand much better the unique pathogenetic mechanisms of COVID-19 compared to other lung infections. The fact that we will do this at single-cell level, offers us the possibility to build trajectories of individual cells and compare these with non-severe versus severe COVID19 versus other infections, and to identify the driver genes underlying the differences.

I think that in these exceptional times collaboration between countries and leading research institutes in Europe is the key. The LifeTime initiative where, for instance, all the single-cell data will be gathered and analysed together is a very nice initiative. I also think that for these types of initiatives the regular administrative paperwork should be minimized. Things as MTAs and GDPR issues should really be minimized. I sometimes find it sad to see that in conference calls about sharing SARS-CoV-2 these things still dominate the discussion. Luckily, we had our COntAGIouS study rapidly approved by our local ethical committee (in 5 days after submission). This is the speed at which we should react to this outbreak.

This is a very good initiative. If we each work on our island, we will have nice findings and publications, but the power of all technologies that are at the core of LifeTime really lies in combining datasets and increasing the number of samples investigated.

"Long-term medical research is crucial because it prepares us for the future"

Interview with Prof. Dr. Mihai Netea, head of the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center, the Netherlands

There are two main priorities for fighting SARS-CoV-2: on the one hand, we need to implement all the measures of public health and respond efficiently from the medical point of view, in order to limit the spread of the epidemics and treat our patients as well as possible, and on the other hand, we have to ensure that we learn as much as possible about the pathophysiology of the diseases in order to design better diagnostic and treatment approaches for the fight against this deadly infection.

Everyone working in the hospital is strongly affected at multiple levels: from the impact that we have seeing so many patients, to long hours of work, to seeing colleagues and friends also becoming sick.

Within our team of infectious diseases specialists, I am strongly involved in developing the protocols and studies related to immunotherapy, especially in sick COVID-19 patients in need of intensive care, in which modulation of hyperinflammation is crucial for prevention and treatment of the acute respiratory distress syndrome (ARDS).

We are performing clinical trials at several levels: firstly, we are investigating the capacity of BCG (bacille Calmette-Guerin) vaccine that induces trained immunity (heterologous protection) to protect against infection with SARS-CoV-2, secondly, I am involved in a large biomarker study for prediction of disease severity, and thirdly we are developing clinical trials using immunomodulatory treatment to prevent that patients with moderate severity to develop severe disease.

Long-term medical research is crucial because it prepares us for the future, to improve therapies and discover more effective ways of prevention. Single-cell technologies are a crucial tool in our armamentarium against diseases: it enables us on the one hand to discover the most important pathophysiological mechanisms in disease, and on the other hand is a crucial too, to define the endotypes of disease that will lead to stratification of patients for personalized therapy.

Two types of research will be needed: on the one hand, it is necessary to continue the search for better vaccines and therapies against the infection, but on the other hand, a very solid research agenda to understand the disease in-depth on the mechanistic level is also necessary.

The LifeTime community can play a crucial unifying role in the landscape of European research. The researchers from the LifeTime community have the unique expertise in single-cell technologies and systems biology, which are crucial for being able to understand the infection with SARS-CoV-2 and to move towards better diagnostics and therapy.

In addition, LifeTime had established a working group on infectious disease to prepare a Roadmap for the future and pneumopathies were identified as important, it has thus been natural to further focus on COVID19. I am part of this action and a taskforce is currently actively engaged on this.

One newly-described property of the immune responses is the capacity to build immunological memory in innate immune cells, a process which was called ‘trained immunity’. Trained immunity is mediated by epigenetic, transcriptional and functional reprogramming of myeloid cell progenitors in the bone marrow. This property of some vaccines such as BCG to induce trained immunity has been shown to be associated with heterologous protection against respiratory tract infections, including viral infection. Several clinical trials are now ongoing that are testing the hypothesis whether the induction of trained immunity by BCG can protect against COVID-19.

I run the HIRI, the Helmholtz Institute for RNA-based Infection Biology, which was founded a few years ago to better understand the role of RNA in infection. SARS-CoV-2 Corona is an RNA virus, it is infecting people around the world, and one of the most promising technologies for defeating this virus is mRNA vaccines. Several of our teams started work on the virus early on. For instance, Neva Caliskan investigates ribosomal frameshifting of SARS-CoV-2, trying to shed light on how the virus’ proteins are made. In line with the LifeTime innovative approach combining breakthrough technologies to understand and target human cells, Emmanuel Saliba is using single-cell RNA-seq to obtain time-resolved expression maps for individual infected cells. This can lead to the identification of new biomarkers and treatments enabling interception of the disease before it becomes too challenging. In short, the mission of our institute and the scientific interest of many of our researchers could not be closer to the COVID-19 pandemic.

We need to fully understand the course of the infection as well as the ensuing host response to help healthcare professionals to treat high-risk patients. The analysis of virus-host interactions on the single-cell level could be key, it would allow us to pinpoint molecular factors and cellular pathways for prioritizing drug targets. Most importantly, however: we need a vaccine soon. I think that this is the time for RNA therapeutics, in this very case mRNA vaccines, to show their full potential.

From previous RNA virus outbreaks, we know that the majority of novel RNA viruses are of animal origin. Databases of viral sequences from wild animals help us trace the natural reservoir by comparative analysis. This may help to predict or even prevent further outbreaks. In fact, the presence of a large reservoir of SARS-CoV-like viruses in horseshoe bats was identified as a major potential health threat more than a decade ago.

Furthermore, basic science into RNA viruses sets the frame for the identification of good antiviral targets, for instance, polymerases, proteases or envelope proteins. At the same time, this research helps us to identify good antigens for vaccines, which – in my view – are the most effective way forward to prevent such pandemics. Vaccines often only become available after the peak of an infection, however. It is thus of great importance to speed up their development especially in the field of RNA-based vaccines.

As said above already, I think that this is the time for mRNA vaccines to prove their enormous potential. It has taken decades of basic research to be able to make and deliver mRNAs — which are bulky molecules — to immune cells for those then to produce a viral protein of interest, with the hope that the patients become immune against the virus. Such mRNA vaccines promise to have many advantages over conventional vaccines: if everything works, they can be developed, tested and produced in much less time than what is currently standard.

Other RNA techniques such as single-cell RNA sequencing will help to monitor whether the vaccine works the way it should, and help us to understand why the virus in some people is more severe than in others. The same goes for testing the effects of antivirals. Using such data, we may understand better the determinants for virus entry in affected tissue.

The combination of these RNA sequencing techniques with advanced machine learning will in the future potentially allow us to predict disease outcomes and thus help healthcare professionals to stratify patients. In addition, we hope to identify RNA molecules, which are vital for the virus. In that case, we would have a unique opportunity to target the virus with specific compounds and enable the development of novel drugs.

In my view, the European Commission should increase science spending and in particular improve the monetary situation for infection research. Infectious diseases are too often considered a thing of the past, but we can now see before our eyes how a tiny virus can paralyze entire continents and cause human and economic losses of a scale that has had no liking in recent times. Importantly, funding of large scale trans-national consortia such as LifeTime is a crucial factor to foster the collaboration of researchers and clinicians in this area in Europe. Connection and coordination across all the necessary research fields is key to win the current fight while making sure we build the infrastructure ensuring preparedness for any future pandemics.

"We need to better understand how human beings and their immune system fight this virus"

There is no doubt that most of us, who have lived a normal life for the last decades, have not experienced such a dramatic situation. This coronavirus is dangerous, it spreads very fast and with the enormous mobility of our modern times, we now have to learn that this virus travels around the world in days and weeks, not months. Furthermore, since this crisis is not only a medical crisis, but comes with secondary effects on our economies, our whole societies, we probably cannot even estimate its true magnitude as of today. Clearly, we need to rethink many things, once we have managed the acute phase of this crisis and this does not only include life and medical sciences, this will include almost all parts of our modern lives.

This is probably one of the few bright spots, I think that the international scientific and medical communities has never been faster, connecting basic and translational researchers, together with clinicians, and pulling things together. Currently in the spotlight are the many attempts to develop new vaccines against the infection and similarly important is the search for new drugs inhibiting the virus or reducing clinical symptoms. These efforts need to be supported and accelerated as much as we can.

But we also need to understand that the only thing that can fight the virus in absence of vaccines and drugs is the human immune system. Unfortunately, we do not know enough about the immune response against this new virus. We also do not understand why the immune system seems to work in most patients, those with few symptoms, and why it fails so miserably in those with severe symptoms and those who died. This knowledge can be used to help select which currently available drugs or therapies would benefit patients and help reduce the pressure on health systems, while the search for a vaccine or drugs inhibiting the virus is ongoing. Here the expertise and the scientific and technological power of the members of LifeTime could really help to decipher the interaction of this virus with their host, namely us human beings. Using the LifeTime’ approach would help identify individuals at risk of developing severe symptoms and guide treatments based on identified biomarkers, while at the same time conduct research to systematically identify new drug targets and vaccine strategies.

LifeTime was initially designed to shape the path towards precision medicine in Europe by bringing together the best brains to determine within a decade how we can leverage our technological and scientific advances for medicine. From the beginning, it was clear that infectious diseases would play an important part in this program, because LifeTimers were convinced from the beginning that infections are a major threat to our citizens’ health, and can lead to lifelong effects after the acute infection. As a short term response to this pandemic, members of LifeTime are also involved in ramping up testing capacities for viral diagnostics, because they have the technical capacity and the respective knowledge, as well as identifying how current patients can be treated. LifeTime itself is designed to identify cellular and molecular biomarkers that can also guide the development of innovative precise treatments based on the understanding of diseases over time in many patients.

While the project was planned for a decade, LifeTimers are also engaged actively in projects to better understand the course of this devastating infectious disease right now. We have been already working hard to adapt our plans to cope with the much more urgent situation we are facing now. We are already asking ourselves: how can we leverage our novel technologies and approaches to faster learn about this disease now? As this crisis will not be gone in a couple of days or weeks, LifeTime members are preparing for tackling the many open questions of this disease that we will have to understand during the next months and that would help to address similar outbreaks in the future.

I am convinced that the search for vaccines, for faster diagnostics tools and curative treatments is of the highest priority. And we fully support our national governments and the European Commission pursuing exactly this goal.

But we need to remember that there is still no guarantee that these searches will be all successful. As I eluded to already, at the moment, the only system fighting this virus efficiently is our human immune system and it will be of utmost importance to understand all these complex interactions between the virus, immune cells and other cells within our body that decide between cure and immunity on the one hand and devastating disease and death on the other hand. At the moment, we do not know enough about this battle and this is exactly what the members of LifeTime want to achieve with novel and innovative technologies that allow us to monitor these complex mechanisms over time in high-resolution.

So, we also need projects that address questions such as which immune cells and immune mediators are involved in the immune response against SARS-CoV-2, when are these operative? Which molecular mechanisms are involved? How do these cells interact with non-immune cells in their environment? What influences the natural history of the disease? Can we manipulate the immune system to change the outcome of the patient? And if so, can we transform this knowledge into new immunotherapies? We will generate lots and lots of data, clinical data, research data, genomics data. Can we utilize the most cutting-edge mathematics, data science, and artificial intelligence to help us make sense of this avalanche of data and be more successful in intercepting the disease? These are some of the burning questions to be answered, but there are many more.

Currently we are in the very acute phase of the pandemics and saving lives with classical methods on intensive care units is of highest priority. But even there, it will be important to guide treatment plans and strategies by a better understanding of the pathophysiology of the disease. So even for these situations it is important to apply cutting edge science and technology to better understand COVID-19.

We also can learn from China where the acute situation seems to be over, but the overall crisis is certainly not yet over. For example, we do not know if enough people have been infected and developed immunity. We also do not know how long immunity lasts and whether this immunity can be boosted by re-infections. So even in this phase, we need to develop programs that monitor how the immune system copes with viruses such as SARS-Cov-2 over time. This is something LifeTime was built for.

And lastly, even if we overcome SARS-Cov-2 completely, humankind needs to prepare for the appearance of similar viruses in the future. History and our virologists taught us this already, and they were right. So, it is worth every effort, to invest in programs such as LifeTime that build the foundation for very strong science, cutting-edge technology development and that bring expertise from many institutions across Europe together to tackle current and future threats on all our people’s health.

Background images by Spencer Phillips/EMBL-EBI

This project has received funding from the European Union’s Horizon 2020 research and innovation framework programme under Grant agreement 820431.